caa a22 4500 397575432 CHVBK 20180308164854.0 cr unu---uuuuu 161202e199609 xx s 000 0 eng 10.1093/hmg/5.9.1325 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.9.1325 Genetic Variation at a Splicing Branch Point in Intron 9 of the Low Density Lipoprotein (LDL)-Receptor Gene: A Rare Mutation that Disrupts mRNA Splicing in a Patient with Familial Hypercholesterolaemia and a Common Polymorphism [Elektronische Daten] [Julie C. Webb, Dilip D. Patel, Carol C. Shoulders, Brian L. Knight, Anne K. Soutar] Mutations in the coding sequence, splice junctions or promoter of the gene for the low density lipoprotein (LDL) receptor are known to be the underlying cause of familial hypercholesterolaemia (FH), but mutations of this type cannot be identified in all patients with a clinical diagnosis of FH. We show here that minor sequence changes elsewhere in introns can be deleterious. A minor rearrangement 30 bp upstream from the junction of intron 9 with exon 10 was detected as a heteroduplex in amplified genomic DNA from one out of 300 heterozygous FH patients. The mutation destroys the only consensus sequence for a splicing branch point in intron 9 and analysis of mRNA from cells from the patient showed that it causes retention of intron 9 or, more rarely, in the use of cryptic splice sites in exon 10. The effect of the mutation on mRNA splicing was confirmed by analysis of mRNA in cells transfected with LDL-receptor mini-gene constructs expressing exons 9 and 10, together with the normal or mutant intron 9. A common C/T polymorphism within this branch point in intron 9 of the LDL-receptor gene does not affect mRNA splicing in vitro and is not associated with significant differences in mean plasma cholesterol concentration in a healthy population. © 1996 Oxford University Press Webb Julie C. MRC Lipoprotein Team, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK aut Patel Dilip D. MRC Lipoprotein Team, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK aut Shoulders Carol C. Molecular Medicine Group, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK aut Knight Brian L. MRC Lipoprotein Team, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK aut Soutar Anne K. MRC Lipoprotein Team, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK aut Human Molecular Genetics Oxford University Press 5/9(1996-09), 1325-1331 0964-6906 5:9<1325 1996 5 hmg https://doi.org/10.1093/hmg/5.9.1325 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.9.1325 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Webb Julie C. MRC Lipoprotein Team, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK aut NATIONALLICENCE 700 1- Patel Dilip D. MRC Lipoprotein Team, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK aut NATIONALLICENCE 700 1- Shoulders Carol C. Molecular Medicine Group, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK aut NATIONALLICENCE 700 1- Knight Brian L. MRC Lipoprotein Team, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK aut NATIONALLICENCE 700 1- Soutar Anne K. MRC Lipoprotein Team, Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/9(1996-09), 1325-1331 0964-6906 5:9<1325 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford